in patients, facilitating microbe invasion leading
to potentiated systemic immune activation (131).
Enhanced Trp to Kyn metabolism during infection contributes to both immune suppression and
to the loss of memory T cells (132).
Conclusions and future perspectives
As the role of Kyn metabolites continues to be
explored in different physiologic and disease settings, the relevance of these compounds as important integrators of environmental, metabolic,
and immune system signals continues to emerge.
In this context, understanding the importance of
the gut microbiome for controlling Trp availability and Kyn metabolism could be crucial to
better understanding interindividual variability
in interpreting nutritional cues. In addition, recruiting skeletal muscle through exercise training
to enhance Kyn clearance and improve mental
health could have additional, still unknown, consequences. In this context, it is tempting to speculate that situations where skeletal muscle oxidative
capacity and PGC-1a1 are reduced (such as with
aging or metabolic disease) could negatively affect
the KP. Interestingly, there are several known
PPAR agonists, which could be explored as potential therapeutic agents to activate the KP in
skeletal muscle. This could have applications not
only in stress-induced depression but also in other
situations where reducing the Kyn burden would
be beneficial—for example, as cytostatic drugs,
where the benefit would be several fold. Inhibition
of the KP would allow for tumor cells that escape
immune surveillance to be properly recognized.
Additionally, the same intervention could interfere with cell proliferation, angiogenesis, and metastatic potential and at the same time deprive the
tumor of energy by reducing NAD+ production. It
may seem that inhibition of a single pathway addresses the majority of cancer progression hallmarks.
As the interest in Kyn metabolites grows, it
becomes clear that where you find them conditions
their biological activity. While exploring their
role in the brain and processes affecting mental
health, kynurenines are being rediscovered in
peripheral tissues where they induce local and
systemic adaptations in both health and disease.
We expect the tales of these metabolites to grow
in the years to come.
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Fig. 4. Activity, uptake, and conversion of tryptophan and its metabolites in peripheral tissues during disease states and challenges to